The present invention relates to a novel composition useful in the treatment of alopecia female hirsutism or seborrhea or in the prevention of bone metastasis caused by prostatic cancer.
Excessive stimulation of androgenic hormones such as dihydrotestosterone (DHT) causes androgen-dependent alopecia (male pattern baldness or the like), acne vulgaris, seborrhea, female hirsutism, benign prostatic hypertrophy and prostatic cancer.
Steroidal anti-androgenic hormones (e.g. female hormone estrogen) are compounds which were found to be capable of treating these symptoms caused by excessive stimulation of androgenic hormones. However, they tend to bring about undesirable activities, for example, feminization, because they themselves have hormonal activity.
On the other hand, nonsteroidal anti-androgenic hormones have also been developed. In spite of being free from hormonal action, they compete with natural androgens for a receptor and therefore have undesirable activities such as feminization of a male fetus in the uterus or of a male, or initiation of a feedback mechanism so as to excessively stimulate the testis.
As 5xcex1 reductase acts on testosterone to form dihydrotestosterone (DHT), if the activity of 5xcex1 reductase can be inhibited, treatment of symptoms due to excessive stimulation of androgenic hormones without said side effects can be expected.
Human 5xcex1 reductase includes two isozymes. It has been elucidated that type I 5xcex1 reductase exists in the sebaceous glands of the face and skin, and that type II 5xcex1 reductase is distributed in the prostate.
It was expected that strong inhibition of type I 5xcex1 reductase existing in the hair follicle would alleviate male panem baldness. The effects of MK386, a selective inhibitor of type I 5-xcex1-reductase, were evaluated using a monkey which was a model animal of male pattern baldness. As a result, the DHT level in the blood showed a 30 to 40% decrease, but such effectiveness of MK 386 was not recognized (J. Invest. Dermatol., 104, 658(1995)). 
Administration of Finasteride, which is a selective inhibitor of type II 5xcex1-reductase, to the model animal at a dose of 1 mg/kg decreased the DHT level in blood by 60 to 70%, however it was unexpectedly recognized that it was effective in the treatment of baldness (J. Clin. Endocrinol. Metabol., 79, 991(1994)).
In fact, the effects of Finasteride on human baldness have been recognized by a clinical test. The inhibition of a factor which participates in the reduction in the size of hair follicles results in such effects and it is presumed to depend on the DHT level in the blood. In addition, it has been found as a result of recent clinical tests that the strength of lowering the DHT level in the blood mainly depends on the strength of the inhibitory activity against type II 5xcex1 reductase, and that better results can be obtained by use of an inhibitor of type I 5xcex1 reductase in combination with that of type II 5xcex1 reductase (J. Clin. Endocrinol. Metabol., 81, 2942-2947(1996)).
Also in the treatment of female hirsutism or seborrhea, a compound having inhibitory activity against type I 5xcex1-reductase and that against type II 5xcex1-reductase is considered to become superior, as a remedy, to a compound having only inhibitory activity against type II 5xcex1-reductase. In order to find a more effective medicament for alopecia, female hirsutism or seborrhea, a compound which inhibits type II 5xcex1-reductase more strongly than Finasteride and at the same time strongly inhibits type I 5xcex1-reductase has been required.
Type II 5xcex1-reductase is distributed in the prostate, so a compound having strong inhibitory activity against type II 5xcex1-reductase is effective for the treatment of prostatic cancer, but it has been found recently that during the development of prostatic cancer and bone metastasis, type I 5xcex1-reductase is in the active form [Japanese Patent Application (kokai) No. Hei 8-277220]. The compound as described above which is capable of inhibiting both of type I and type II 5xcex1-reductases is also expected to be useful in the prevention and treatment of prostatic diseases.
The compound (I) of the present invention has been disclosed to have strong inhibitory activity against prostatic enzymes [Japanese Patent Application (kokai) Hei 5-326931. It is reasonable to expect inhibitory activity against type II 5xcex1-reductase from the inhibitory activity against prostatic enzymes. However it is impossible to expect inhibitory activity against type I 5xcex1-reductase, because type I 5xcex1-reductase is not distributed in the prostate.
The present inventors carried out an extensive investigation for many years on the synthesis of derivatives having inhibitory activity against testosterone 5xcex1-reductase and the pharmacological activity of the derivatives. As a result, it has been found that some compounds having a specific structure strongly inhibit type II 5xcex1-reductase and moreover strongly inhibit type I 5xcex1-reductase, and therefore they exhibit strong DHT blood level lowering activity which has not been available so far among known type II selective 5xcex1-reductase inhibitors, and that they are useful in the treatment of alopecia, female hirsutism or seborrhea or in the prevention of the bone metastasis caused by prostatic cancer.
The present invention provides a novel composition useful in the treatment of alopecia, female hirsutism or seborrhea or in the prevention of bone metastasis caused by prostatic cancer. In another aspect, the present invention provides a use of said compound for the preparation of a composition for the treatment of alopecia, female hirsutism or seborrhea or a composition for the prevention of bone metastasis caused by prostatic cancer.
In still another aspect, the present invention provides a method for treating alopecia, female hirsutism or seborrhea or for preventing bone metastasis caused by prostatic cancer, which comprises administering a therapeutically effective amount of said compound to a warm-blooded animal in need of such treatment.
The novel composition for the treatment of alopecia of the present invention, female hirsutism or Seborrhea or for the prevention of bone metastasis caused by prostatic cancer comprises, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, preferably N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5xcex1-androst-1-ene-17xcex2-carboxamide.
The inventive method administers a compound represented by formula (I) or a pharmaceutically acceptable salt or ester or hydrate thereof for the treatment of alopecia, female hirsutism or seborrhea or the prevention of bone metastasis caused by prostatic cancer. Preferably N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5xcex1-androst-1-ene-17-xcex2-carboxamide for the preparation of said composition is used. 
(wherein, R1 and R2 are the same or different from each other and each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group or a lower alkoxy group).
In the formula (I), the term xe2x80x9clower alkoxy groupxe2x80x9d means a straight chain or branched chain C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy, of which a straight or branched C1-4 alkoxy group is preferred, and a methoxy group is more preferred.
The term xe2x80x9calopeciaxe2x80x9d means male pattern baldness and female head alopecia.
Since compound (I) can form a salt, the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d means the salts of the compound (I) of the present invention which can be converted to salts thereof, examples of such salts preferably include alkali metal salts such as a sodium salt, a potassium salt and a lithium salt, alkaline earth metal salts such as a calcium salt and a magnesium salt, and metal salts such as a aluminum salt, an iron salt and a zinc salt.
When the compound (I) of the present invention is allowed to stand in the atmosphere, it may absorb water thereto or to form a hydrate. Such a substance is also embraced in the present invention.
The xe2x80x9cprotecting groupxe2x80x9d of the term xe2x80x9cprotected hydroxyl groupxe2x80x9d means xe2x80x9cconventional protecting groupxe2x80x9d or a xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d.
The xe2x80x9cconventional protecting groupxe2x80x9d means a protecting group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
Preferred examples of the xe2x80x9cconventional protecting groupxe2x80x9d for the hydroxyl group include xe2x80x9clower aliphatic acyl groupsxe2x80x9d for example, lower alkylcarbonyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecaroyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl and henicosanoyl, carboxyl-substituted alkylcarbonyl group such as succinoyl, glutanoyl and adipoyl, haloger-substituted alkylcarbonyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, lower alkoxy-substituted alkylcarbonyl group such as methoxyacethyl, unsaturated alkylcarbonyl group such as (E)-2-methyl-2-buthenoyl; xe2x80x9caromatic acyl groupsxe2x80x9d for example, arylcarbonyl group such as benzoyl, xcex1-naphthoyl and xcex2-naphthoyl, halogenated arylcarbonyl group such as 2-bromobenzoyl and 4-chloro-benzoyl, lower alkyl-substituted arylcarbonyl group such as 2,4,6-trimethyl-benzoyl and 4-toluoyl, hydroxy-substituted arylcarbonyl group such as 3,5-dimethyl-4-hydroxybenzoyl and 3,5-di-t-butyl-4-hydroxybenzoyl, lower alkoxy-substituted arylcarbonyl group such as 4-anisoyl group, nitro-subatituted arylcarbonyl group such as 4-nitrobenzoyl and 2-nitro-benzoyl, lower alkoxycarbonyl-substituted arylcarbonyl group such as 2-(methoxycarbonyl)benzoyl group; aryl-substituted arylcarbonyl group such as 4-phenylbenzoyl group; xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupsxe2x80x9d such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl; xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupsxe2x80x9d such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; xe2x80x9csilyl groupsxe2x80x9d, for example, tri(lower alkyl)silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl and triisopropylsilyl and tri (lower alkyl) silyl group substituted with 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl; xe2x80x9calkoxymethyl groupsxe2x80x9d, for example, lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl, lower alkoxymethyl groups substituted with lower alkoxy such as 2-methoxyethoxymethyl and (halogeno lower alkoxy)methyl groups such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; xe2x80x9csubstituted ethyl groupsxe2x80x9d, for example, ethyl group substituted with lower alkoxy such as 1-ethoxyethyl and 1-(isopropoxy)ethyl and halogenated ethyl groups such as 2,2,2-trichloroethylxe2x80x9d; xe2x80x9caralkyl groupsxe2x80x9d, for example, lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl and lower alkyl groups each substituted with 1 to 3 aryl groups having an aryl substituted with a lower alkyl, halogeno (lower alkyl), lower alkoxy, nitro, halogen or cyano group such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 3,5-di(trifluoromethyl)benzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; xe2x80x9clower alkoxycarbonyl groupsxe2x80x9d such as methoxycarbonyl, ethoxycarbonyl, tert-buthoxycarbonyl and isobuthoxycarbonyl,; xe2x80x9clower alkenyloxycarbonyl groupsxe2x80x9d such as vinyloxycarbonyl and allyloxycarbonyl; and xe2x80x9caralkyloxycarbonyl groupsxe2x80x9d, for example, aryl substituted with 1 or 2 lower alkoxy or nitro group such as 4-methoxylbenzyloxycarbonyl, 3,4-dimethoxylbenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.
The xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d means a protecting group which is cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. It can be determined whether an ester is such a derivative by administering it to an experimental animal, such as a rat or mouse, by intravenous injection, examining the body fluid of the animal after administration and detecting an original compound or a pharmaceutically acceptable salt thereof.
Preferred examples of the xe2x80x9cprotecting group which can be cleaved in vivo by a biological method such as hydrolysisxe2x80x9d for the hydroxyl group include 1-(acyloxy) xe2x80x9clower alkyl groupsxe2x80x9d, for example, 1-(xe2x80x9clower aliphatic acylxe2x80x9d oxy) xe2x80x9clower alkyl groupsxe2x80x9d such as formyloxymethyl, acetoxymethyl, dimethylamincacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl, 1-(xe2x80x9ccycloalkylxe2x80x9d carbonyloxy) xe2x80x9clower alkyl groupsxe2x80x9d such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl, and 1-(xe2x80x9caromaticacylxe2x80x9d oxy) xe2x80x9clower alkyl groupsxe2x80x9d such as benzoyloxymethyl; (lower alkoxycarbonyloxy) alkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(tert-butoxycarbonyloxy) ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy) propyl, 1-(cyclohexyloxycarbonyloxy) propyl, 1-(cyclopentyloxycarbonyioxy) butyl 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl, 2-(propoxycarbonyloxy)ethyl, 2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl, 2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl, 2-(hexyloxycarbonyloxy) ethyl, 1-methoxycarbonyloxy) propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy) propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl; and oxodioxolenylmethyl groups such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylpheyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlarophenyl) -2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl: xe2x80x9cphthalidyl groupsxe2x80x9d such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl: the above-described xe2x80x9clower aliphatic acyl groupsxe2x80x9d : the above-described xe2x80x9caromatic acyl groupsxe2x80x9d: xe2x80x9chalf ester salt residue of succinic acidxe2x80x9d: xe2x80x9cphosphate salt residuexe2x80x9d: xe2x80x9cester forming residues such as with amino acidsxe2x80x9d: carbamoyl groups: carbamoyl group substituted with 1 or 2 lower alkyl groups: and xe2x80x9c1-(acyloxy)alkyloxycarbonyl groupsxe2x80x9d such as pivaloyloxynethyloxycarbonyl, of which the xe2x80x9ccarbonyloxyalkyl groupsxe2x80x9d are preferred. Pharmacologically acceptable esters are preferred.
The compound (I) of the present invention may be prepared by the process shown below. 
(wherein, R1 and R2 are as described above).
In Process A, a compound (I) is prepared by the condensation of a carboxylic acid derivative with an amine derivative.
In step A1, a compound (I) is prepared using a compound (II) or a reactive derivative thereof and a compound (III). This step is carried out in a conventional manner used in peptide synthesis, for example, an azide process, an active ester process, a mixed acid anhydride process or a condensation process.
Among these processes the azide process comprises treating an azide compound with an amine compound (III). The azide compound is prepared by the reaction of nitrous acid with a hydrazide of an amino acid, which is obtained by a reaction of compound (II) or an ester thereof with hydrazine at around room temperature in an inert solvent (e.g. dimethylformamide).
Examples of the nitrous acid compound as used herein include alkali metal nitrites such as sodium nitrite and alkyl nitrites such as isoamyl nitrite.
The reaction is effected preferably in an inert solvent and examples of the solvent as used herein include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide and pyrrolidones such as N-methylpyrrolidone. The two step reaction of this process is carried out ordinarily in one pot. The reaction temperature ranges from xe2x88x9250xc2x0 C. to 0xc2x0 C. in the first step, while it ranges from xe2x88x9210xc2x0 C. to 10xc2x0 C. in the second step. The time required for reaction ranges from 5 minutes to 1 hour in the first step, while it ranges from 10 hours to 5 days in the second step.
The active ester process is carried out by reaction of the compound (II) with an active esterifying agent to form the active ester of the compound (II) and then by reaction of the resulting compound with the amine compound (III).
Both the reactions are carried out preferably in an inert solvent and examples of the solvent as used herein include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide and nitriles such as acetonitrile.
Examples of the esterifying agent as used herein include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxyimide and disulfide compounds such as dipyridyl disulfide. The esterification is suitably effected in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.
The reaction temperature ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. in the esterification while it is around room temperature in the reaction of the active ester compound with the amine (III). The time necessary for the reaction ranges from 30 minutes to 80 hours in each of the reactions.
In the reaction of an active ester with an amine, 4-dimethylaminopyridine or the like can be added.
The mixed acid anhydride process is carried out by reaction of a mixed acid anhydride of compound (II) with an amine.
The reaction for preparing the mixed acid anhydride is achieved by reaction of a compound (II) with an agent forming a mixed acid anhydride. Examples of such an agent include a lower (C1-C4) alkyl halogenated carbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate, a lower alkanoyl halide such as pivaloyl chloride, a (lower alkyl)- or diary1-cyanophosphoric acid such as diethyl cyanophosphoric acid or diphenyl cyanophosphoric acid, or a sulfonyl halide such as 2,4.6-triisopropylbenzenesulfonyl chloride, paratoluenesulfonyl chloride or methanesulfonyl chloride.
The reaction is carried out suitably in the presence of an organic amine such as trimethylamine or N-methylmorpholine at xe2x88x9210xc2x0 C. to 50xc2x0 C. The time necessary for the reaction ranges from 30 minutes to 20 hours.
The reaction of a mixed acid anhydride and an amine (III) is conducted suitably in an inert solvent (for example, the above-exemplified halogenated hydrocarbon, amide or ether) in the presence of the above-exemplified organic amine. The reaction temperature ranges from 0xc2x0 C. to 80xc2x0 C. and the time necessary for the reaction ranges from 1 hour to 48 hours.
Alternatively, process A is carried out in the mixture of a compound (II), a compound (III) and an agent forming the corresponding mixed acid anhydride without isolation of the mixed acid anhydride.
The condensation process is carried out by directly reacting the compound (II) with the amine (III) in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, 1-methyl-2-chloro-pyridinium iodide-triethylamine. This reaction is carried out under conditions similar to those employed in the above-described reaction for the preparation of an active ester.
When R1 or R2 contains a protected hydroxyl group, the protecting group can be removed in a conventional manner.
Starting compound (II) or active ester thereof is a known compound or prepared by a procedure familiar to those skilled in the art [for example, J. Med. Chem., 27, 1690(1984); J. Med. Chem., 29, 2298(1986)].
Compound (III) is a known compound or prepared by one skilled in the art (for example,
Synthesis, 593(1976);
J. Org. Chem., 36, 305(1971);
Angew. Chem., 82, 138(1970);
Synthesis, 24(1978);
Synthetic Commun., 18, 777(1988);
Synthetic Commun., 18, 783(1988);
Organic Reaction, 3, 337(1946);
Org. Synthesis, 51, 48(1971);
Tetrahedron, 30, 2151(1974);
J. Org. Chem. 37, 188(1972)]. For example, H2Nxe2x80x94C(Me)(Me)xe2x80x94Ph(R1)(R2) which is a starting compound of the present invention can be prepared as shown in the following reaction scheme: 
(wherein,
R1 and R2 are as described above.
Me represents a methyl group and Ph represents a phenyl group) by Grignard reaction, substitution reaction of a hydroxyl group with azide group and then reduction of azide group in a similar process to that described in Synthesis. 24(1978).
Compound (I) is administered orally in the form of tablets, capsules, granules, powders, syrups or the like and locally in the form of an ethanol solution, cleansing foam, cleansing cream, skin gel, skin lotion, shampoo gel, cream shampoo or the like.
Oral pharmaceutical formulations are prepared by procedures familiar to those skilled in the art by using excipients (examples include organic excipients, e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose and sodium internally cross-linked carboxymethyl cellulose; gum arabic; dextran; and pullulan; and inorganic excipients. e.g., silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate, phosphates such as calcium phosphate; carbonates such as calcium carbonate and sulfates such as calcium sulfate), lubricants (examples include stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salts of aliphatic acid; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicic hydrate; and the above-exemplified starch derivatives), binders (examples include polyvinyl pyrrolidone, Macrogol and compounds similar to the above-exemplified excipients), disintegrants (examples include compounds similar to the above-exemplified excipients and chemically-modified starches and celluloses such as sodium cross carmellose, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone), stabilizers (examples include paraoxybenzoates such as methyl paraben; and propyl paraben, alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid, and sorbic acid), corrigents (examples include ordinarily-employed sweeteners, acidifiers and flavors) and/or diluents.
Local pharmaceutical formulations are prepared by adding an exemplified compound to a base well known to those skilled in the art; for example, suspending agents (examples include gum arabic, tragacanth, methyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate and bentonite), emulsifying agents (examples include triethanolamine, sodium lauryl sulfate, sorbitan sesquioleate, polysorbate 80 and stearic acid polyoxyl 40), moistening agents (examples include sorbitol, ethylene glycol, propylene glycol, butylene glycol and glycerin), preservatives (examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and butyl paraoxybenzoate) or solvents (examples include water; alcohols such as ethanol, isopropyl alcohol, propylene glycol, cetanol and isostearyl alcohol; hydrocarbons such as natural fats and oils, waxes and liquid paraffin; aliphatic acids such as stearic acid, isostearic acid, oleic acid and linoleic acid; and esters such as isopropyl myristate) or a mixture thereof.
The amount of the compound (I) to be orally administered or locally administered will vary depending on the condition, age or the like of the patient and the specific condition (i.e., alopecia, female hirsutism or seborrhea) which is being treated or the condition which is being prevented (the specified bone metastasis). It is desirably administered in one dose of 0.001 mg/kg weight (preferably 0.01 mg/kg weight) as a lower limit and 10 mg/kg weight (preferably 0.5 mg/kg weight) as an upper limit and administered in a single dose or in several divided doses a day.